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Molecules 2018, 23(5), 1221; https://doi.org/10.3390/molecules23051221

1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors

1
Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
2
Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA
3
Structural Genomics Consortium, Universidade Estadual de Campinas-UNICAMP, Campinas, São Paulo 13083-886, Brazil
4
Center for Molecular and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Cidade Universitária Zeferino Vaz, Avenida Cândido Rondon 400, P. O. Box 6010, 13083-875 Campinas, São Paulo 13083-886, Brazil
5
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, 70211 Kuopio, Finland
6
St Vincent’s Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy 3065, Australia
7
Mary MacKillop Institute for Health Research, Australian Catholic University, 215 Spring Street, Melbourne 3000, Australia
8
The Florey Institute of Neuroscience and Mental Health, Parkville 3052, Australia
9
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
10
Department of Chemistry, University of Cyprus, P. O. Box 20537, 1678 Nicosia, Cyprus
11
Department of Life Sciences, School of Sciences, European University Cyprus, 6 Diogenis Str., Engomi, P. O. Box 22006, 1516 Nicosia, Cyprus
*
Authors to whom correspondence should be addressed.
Academic Editor: Thierry Besson
Received: 29 April 2018 / Revised: 15 May 2018 / Accepted: 15 May 2018 / Published: 19 May 2018
(This article belongs to the Special Issue Focusing on Sulfur in Medicinal Chemistry)
Full-Text   |   PDF [13494 KB, uploaded 19 May 2018]   |  

Abstract

We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype for the design of ATP-competitive kinase inhibitors. Using insights from a co-crystal structure of a 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement of bound water molecules in the active site. Since the TDZ analogues showed reduced promiscuity compared to their 2,4-dianilinopyrimidine counter parts, they represent starting points for development of highly selective kinase inhibitors. View Full-Text
Keywords: thiadiazinone; hinge binder; kinase inhibitor design; kinase water network; CaMKK2 thiadiazinone; hinge binder; kinase inhibitor design; kinase water network; CaMKK2
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Asquith, C.R.M.; Godoi, P.H.; Couñago, R.M.; Laitinen, T.; Scott, J.W.; Langendorf, C.G.; Oakhill, J.S.; Drewry, D.H.; Zuercher, W.J.; Koutentis, P.A.; Willson, T.M.; Kalogirou, A.S. 1,2,6-Thiadiazinones as Novel Narrow Spectrum Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) Inhibitors. Molecules 2018, 23, 1221.

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